Techniques to purify and study normal and tumor stem cells are rapidly improving, yet we still understand relatively little about the signaling pathways that balance stem cell proliferation and self-renewal. One pathway emerging as critical regulator of stem cell maintenance is the PTEN/PI3K pathway. PTEN is the second most frequently mutated tumor suppressor in cancer, and in some murine stem cell models, deleting PTEN is a tumor-initiating event. Thus, understanding the molecular basis of how PTEN/PI3K-dependent pathways regulate the fate of diverse somatic stem cells has broad implications. In this proposal, we use mouse genetics to develop novel models of PTEN/PI3K-dependent signaling pathways in mesenchymal stem cells. Using these models, we will comprehensively define the mechanism by which this pathway controls mesenchymal stem cell fate, tissue homeostasis, and tumor development. Our results will provide key insight into the molecular basis of both normal and tumor stem cell regulation. PUBLIC HEALTH RELEVANCE: The growth of some tumors may be driven by a sub-population of cells that exhibit stem cell characteristics, such as being able to proliferate and self-renew. For other cancers, mutation in a rare stem cell could be the tumor-initiating event. Thus, understanding the molecular regulation of both normal and tumor stem cells has broad clinical implications in the ongoing fight against cancer. In this proposal, we investigate the molecular mechanisms by which normal stem cells are regulated, and ask how deregulation of these mechanisms causes tissue growth disorders and cancer. By better understanding the biology of normal and tumor stem cells, we can more rationally design cancer therapies.